A. Background Regarding Antihistamines
Antihistamines have been shown to be efficacious in the treatment of the symptoms of seasonal allergic rhinitis and in the treatment of itching of the eye associated with allergic conjunctivitis. Examples of antihistamines include, but are not limited to, azelastine hydrochloride (OPTIVAR®), chlorpheniramine maleate (CHLOR-TRIMETON®, PIRITON®), brompheniramine maleate, loratadine (CLARITIN®, ALAVERT®), astemizole (HISMANAL®), diclofenac (VOLTAREN®, CATAFLAM®), terfenadine (SELDANE®) and their salts, prodrugs and esters and combinations thereof. Other examples include Allent® (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Andehist® Syrup (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Bromadrine PD® (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Bromadrine® (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Bromfed® (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Bromfed-PD® (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Bromfenex® (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Bromfenex® PD (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Bromphenirqmine-PSE® (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Dallergy®-JR (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Dexaphen® SA (containing Dexbrompheniramine Maleate and Pseudoephedrine Sulfate), Dimetapp® Cold & Fever (containing Brompheniramine Maleate, Acetaminophen, and Pseudoephedrine Hydrochloride), Dimetapp® Elixir (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Drixoral® Allergy/Sinus (containing Dexbrompheniramine Maleate, Acetaminophen, and Pseudoephedrine Sulfate), Drixoral® Cold & Allergy (containing Dexbrompheniramine Maleate and Pseudoephedrine Sulfate), Drixoral® Cold & Flu (containing Dexbrompheniramine Maleate, Acetaminophen, and Pseudoephedrine Sulfate), Lodrane® (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Lodrane® LD (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Respahist® (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Rondec® Syrup (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), Ultrabrom®D (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride), and Ultrabrom® PD (containing Brompheniramine Maleate and Pseudoephedrine Hydrochloride).
In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors.
Histamine, acting on H1-receptors, produces pruritis, vasodilation, hypotension, flushing, headache, tachycardia, bronchoconstriction, increases vascular permeability, potentiates pain, and more. H1-antihistamines are clinically used in the treatment of histamine-mediated allergic conditions. These indications may include allergic rhinitis, allergic conjunctivitis, allergic dermatological conditions (contact dermatitis), urticaria, angioedema, pruritus (atopic dermatitis, insect bites), anaphylactic or anaphylactoid reactions—adjunct only, nausea and vomiting (first-generation H1-antihistamines), and sedation (first-generation H1-antihistamines). Antihistamines can be administered topically (through the skin, nose, or eyes) or systemically, based on the nature of the allergic condition.
Adverse drug reactions are most commonly associated with the first-generation H1-antihistamines. This is due to their relative lack of selectivity for the H1-receptor. The most common adverse effect is sedation—this “side effect” being utilised in many over the counter (OTC) sleeping-aid preparations. Other common adverse effects in first-generation H1-antihistamines include dizziness, tinnitus, blurred vision, euphoria, uncoordination, anxiety, insomnia, tremor, nausea and vomiting, constipation, diarrhoea, dry mouth, and dry cough. Infrequent adverse effects include urinary retention, palpitations, hypotension, headache, hallucination, and psychosis.
First generation antihistamines include piperoxam, ethylenediamines (mepyramine (pyrilamine), antazoline), ethanolamines (diphenhydramine, carbinoxamine, doxylamine, clemastine, and dimenhydrinate), alkylamines (pheniramine, chlorenamine (chlorpheniramine), dexchlorphenamine, brompheniramine, and triprolidine), piperazines (cyclizine, hydroxyzine, and meclizine), and tricyclics (promethazine, alimemazine (trimeprazine), cyproheptadine, and azatadine).
The newer second-generation H1-antihistamines are far more selective for peripheral histamine H1-receptors and, correspondingly, have a far improved tolerability profile compared to the first-generation agents. The most common adverse effects noted for second-generation agents include drowsiness, fatigue, headache, nausea and dry mouth. Second-generation antihistamines include systemic drugs (acrivastine, astemizole, cetirizine, loratadine, mizolastine, and terfenadine), topical drugs (azelastine, levocabastine, and olopatidine),
Third generation antihistamines are the active enantiomer (levocetirizine, desloratadine) or metabolite (fexofenadine) derivatives of second-generation drugs intended to have increased efficacy with fewer adverse drug reactions. For example, fexofenadine is associated with a decreased risk of cardiac arrhythmia as compared to terfenadine. However, there is little evidence for any advantage of levocetirizine or desloratadine, compared to cetirizine or loratadine respectively. Such antihistamines include levocetirizine, desloratadin, and fexofenadine.
Other inhibitors of histamine release include cromoglicate (cromolyn) and nedocromil, H2-receptor antagonists (cimetidine, ranitidine, and famotidine), and H3- and H4-receptor antagonists (thioperamide, clobenpropit, impromidine).
B. Background Regarding Corticosteroids
Corticosteroids have been shown to be effective for the maintenance treatment of asthma as prophylactic therapy, for the management of the nasal symptoms of seasonal and perennial allergic and nonallergic rhinitis in adults and pediatric patients, and for the relief of the signs and symptoms of seasonal allergic conjunctivitis.
1. Corticosteroids Generally
Corticosteroids are drugs closely related to cortisol, a hormone which is naturally produced in the adrenal cortex (the outer layer of the adrenal gland). Corticosteroid drugs include betamethasone (Celestone®, budesonide (Entocort® EC), cortisone (Cortone®, dexamethasone (Decadron®), hydrocortisone (Cortef®), methylprednisolone (Medrol®), prednisolone (Prelone®), prednisone (Cortan®, Deltasone®, Liquid Pred®, Meticorten®, Orasone®, Panasol-S®, Prednicen-M® and Sterapred®), and triamcinolone (Kenacort®, Kenalog®).
Corticosteroids act on the immune system by blocking the production of substances that trigger allergic and inflammatory actions, such as prostaglandins. However, they also impede the function of white blood cells which destroy foreign bodies and help keep the immune system functioning properly. The interference with white blood cell function yields a side effect of increased susceptibility to infection.
Corticosteroids are widely used for many conditions. Corticosteroids are versatile in their mode of application. They can be given orally, orally, injected into the vein or muscle, applied locally to the skin, or injected directly into inflamed joints. Corticosteroid drugs can also be used as ingredients contained in inhalers to treat asthma or bronchial disease and in nasal drops and sprays to treat various nasal problems. Corticosteroids can be used in conjunction with other drugs, and are prescribed for short-term and long-term use.
The potent effect of corticosteroids can result in serious side effects which mimic Cushing's disease, a malfunction of the adrenal glands resulting in an overproduction of cortisol. The list of potential side effects is long and includes increased appetite and weight gain; deposits of fat in chest, face, upper back, and stomach; water and salt retention leading to swelling and edema; high blood pressure; diabetes; black and blue marks; slowed healing of wounds; osteoporosis; cataracts; acne; muscle weakness; thinning of the skin; increased susceptibility to infection; stomach ulcers; increased sweating; mood swings; psychological problems such as depression; and adrenal suppression and crisis. Side effects can be minimized by keeping to the lowest dose possible.
2. Inhalation Corticosteroids
Inhalation corticosteroids are cortisone-like medicines. They are used to help prevent the symptoms of asthma. When used regularly every day, inhalation corticosteroids decrease the number and severity of asthma attacks. However, they will not relieve an asthma attack that has already started.
Inhaled corticosteroids work by preventing certain cells in the lungs and breathing passages from releasing substances that cause asthma symptoms. This medicine may be used with other asthma medicines, such as bronchodilators (medicines that open up narrowed breathing passages) or other corticosteroids taken by mouth. Examples of inhalation corticosteroids currently commercially available include beclomethasone (aerosol, capsules for inhalation, and powder for inhalation); beclomethasone dipropionate HFA (aerosol); budesonide (powder for inhalation and suspension for inhalation); flunisolide (aerosol); and triamcinolone (aerosol).
C. Background Regarding Nanoparticulate Active Agent Compositions
Nanoparticulate active agent compositions, first described in U.S. Pat. No. 5,145,684 (“the '684 patent”), comprise particles of a poorly soluble therapeutic or diagnostic agent having adsorbed onto or associated with the surface thereof a non-crosslinked surface stabilizer. Methods of making nanoparticulate compositions are described, for example, in U.S. Pat. Nos. 5,518,187 and 5,862,999, both for “Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,388, for “Continuous Method of Grinding Pharmaceutical Substances;” and U.S. Pat. No. 5,510,118 for “Process of Preparing Therapeutic Compositions Containing Nanoparticles.”
Nanoparticulate active agent compositions are also described, for example, in U.S. Pat. No. 5,298,262 for “Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;” U.S. Pat. No. 5,302,401 for “Method to Reduce Particle Size Growth During Lyophilization;” U.S. Pat. No. 5,318,767 for “X-Ray Contrast Compositions Useful in Medical Imaging;” U.S. Pat. No. 5,326,552 for “Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” U.S. Pat. No. 5,328,404 for “Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;” U.S. Pat. No. 5,336,507 for “Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;” U.S. Pat. No. 5,340,564 for “Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability;” U.S. Pat. No. 5,346,702 for “Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;” U.S. Pat. No. 5,349,957 for “Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles;” U.S. Pat. No. 5,352,459 for “Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization;” U.S. Pat. Nos. 5,399,363 and 5,494,683, both for “Surface Modified Anticancer Nanoparticles;” U.S. Pat. No. 5,401,492 for “Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents;” U.S. Pat. No. 5,429,824 for “Use of Tyloxapol as a Nanoparticulate Stabilizer;” U.S. Pat. No. 5,447,710 for “Method for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” U.S. Pat. No. 5,451,393 for “X-Ray Contrast Compositions Useful in Medical Imaging;” U.S. Pat. No. 5,466,440 for “Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays;” U.S. Pat. No. 5,470,583 for “Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation;” U.S. Pat. No. 5,472,683 for “Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,500,204 for “Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,518,738 for “Nanoparticulate NSAID Formulations;” U.S. Pat. No. 5,521,218 for “Nanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Agents;” U.S. Pat. No. 5,525,328 for “Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,543,133 for “Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles;” U.S. Pat. No. 5,552,160 for “Surface Modified NSAID Nanoparticles;” U.S. Pat. No. 5,560,931 for “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” U.S. Pat. No. 5,565,188 for “Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles;” U.S. Pat. No. 5,569,448 for “Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions;” U.S. Pat. No. 5,571,536 for “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” U.S. Pat. No. 5,573,749 for “Nanoparticulate Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,573,750 for “Diagnostic Imaging X-Ray Contrast Agents;” U.S. Pat. No. 5,573,783 for “Redispersible Nanoparticulate Film Matrices With Protective Overcoats;” U.S. Pat. No. 5,580,579 for “Site-specific Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly(ethylene Oxide) Polymers;” U.S. Pat. No. 5,585,108 for “Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays;” U.S. Pat. No. 5,587,143 for “Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for Nanoparticulate Compositions;” U.S. Pat. No. 5,591,456 for “Milled Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer;” U.S. Pat. No. 5,593,657 for “Novel Barium Salt Formulations Stabilized by Non-ionic and Anionic Stabilizers;” U.S. Pat. No. 5,622,938 for “Sugar Based Surfactant for Nanocrystals;” U.S. Pat. No. 5,628,981 for “Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents;” U.S. Pat. No. 5,643,552 for “Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,718,388 for “Continuous Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,919 for “Nanoparticles Containing the R(−)Enantiomer of Ibuprofen;” U.S. Pat. No. 5,747,001 for “Aerosols Containing Beclomethasone Nanoparticle Dispersions;” U.S. Pat. No. 5,834,025 for “Reduction of Intravenously Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions;” U.S. Pat. No. 6,045,829 “Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;” U.S. Pat. No. 6,068,858 for “Methods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;” U.S. Pat. No. 6,153,225 for “Injectable Formulations of Nanoparticulate Naproxen;” U.S. Pat. No. 6,165,506 for “New Solid Dose Form of Nanoparticulate Naproxen;” U.S. Pat. No. 6,221,400 for “Methods of Treating Mammals Using Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors;” U.S. Pat. No. 6,264,922 for “Nebulized Aerosols Containing Nanoparticle Dispersions;” U.S. Pat. No. 6,267,989 for “Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions;” U.S. Pat. No. 6,270,806 for “Use of PEG-Derivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions;” U.S. Pat. No. 6,316,029 for “Rapidly Disintegrating Solid Oral Dosage Form,” U.S. Pat. No. 6,375,986 for “Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate;” U.S. Pat. No. 6,428,814 for “Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers;” U.S. Pat. No. 6,431,478 for “Small Scale Mill;” U.S. Pat. No. 6,432,381 for “Methods for Targeting Drug Delivery to the Upper and/or Lower Gastrointestinal Tract;” U.S. Pat. No. 6,582,285 for “Apparatus for Sanitary Wet Milling;” and U.S. Pat. No. 6,592,903 for “Nanoparticulate Dispersions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate;” U.S. Pat. No. 6,656,504 for “Nanoparticulate Compositions Comprising Amorphous Cyclosporine;” U.S. Pat. No. 6,742,734 for “System and Method for Milling Materials;” U.S. Pat. No. 6,745,962 for “Small Scale Mill and Method Thereof;” U.S. Pat. No. 6,811,767 for “Liquid droplet aerosols of nanoparticulate drugs;” U.S. Pat. No. 6,908,626 for “Compositions having a combination of immediate release and controlled release characteristics;” U.S. Pat. No. 6,969,529 for “Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers;” U.S. Pat. No. 6,976,647 for “System and Method for Milling Materials;” and U.S. Pat. No. 6,991,191 for “Method of Using a Small Scale Mill;” all of which are specifically incorporated by reference. In addition, U.S. Patent Application No. 20020012675 A1, published on Jan. 31, 2002, for “Controlled Release Nanoparticulate Compositions,” describes nanoparticulate compositions and is specifically incorporated by reference. None of these references describe compositions of nanoparticulate corticosteroid in combination with at least one antihistamine.
Amorphous small particle compositions are described, for example, in U.S. Pat. No. 4,783,484 for “Particulate Composition and Use Thereof as Antimicrobial Agent;” U.S. Pat. No. 4,826,689 for “Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds;” U.S. Pat. No. 4,997,454 for “Method for Making Uniformly-Sized Particles From Insoluble Compounds;” U.S. Pat. No. 5,741,522 for “Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;” and U.S. Pat. No. 5,776,496, for “Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter” all of which are specifically incorporated herein by reference.
There is a need for compositions of improved compositions for treating asthma. Current antihistamine compositions and corticosteroid compositions have significant side effects. Compositions having improved bioavailability and lower dosing are therefore highly desirable. The present invention satisfies these needs.